Multiple Sclerosis (MS) is a progressive, immune-mediated primary demyelinating disease of the central nervous system (CNS). Primary demyelination is the pathologic process characterized by the destruction of myelin sheaths with relative maintenance of axons and other neuronal structures. MS is the principal human CNS primary demyelinating disease, although there are other rare forms of demyelinating disease that affect the brain and spinal cord, including Schilder's disease, Balos concentric sclerosis, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalopathy, tropical spastic paraparesis, and human T-cell leukemia virus (HTLV)-I-associated myelopathy.
MS affects scattered areas of the CNS with a predilection for periventricular white matter, brainstem, spinal cord, and optic nerves. The CNS plaques associated with MS are characterized by primary demyelination and death of oligodendrocytes (myelin-producing cells) within the center of the lesion. During the early evolution of the plaque, perivascular inflammatory cells (lymphocytes, plasma cells, macrophages) invade the substance of the white matter and are thought to play a critical role in myelin destruction. This process is followed by extensive gliosis by astrocytes and aberrant attempts at remyelination with oligodendrocytes proliferating at the edges of the plaque. In addition, immunoglobulins are deposited with each plaque.
Although the etiology and pathogenesis of MS is unknown, epidemiologic studies indicate that clinical exacerbations of the disease may be triggered by a virus. Under this hypothesis, the destruction of myelin or oligodendrocytes may result from an immune attack directed against self or against novel antigen plus self, which is triggered by the virus. See Rodriguez, Multiple Sclerosis: basic concepts and hypothesis, Mayo Clin. Proc., 64:570-6 (1989).
Viruses from many families and subfamilies (Herpetoviridae, Coronaviridae, Picornaviridae, Lentiviridae, Paramyxoviridae, Togaviridae) experimentally induce demyelination in animals of various species (e.g., mice, rats, dogs, sheep). Dal Canto et al., Ann. Neurol., 11:109 (1982). Epidemiologic studies based on migration data and differences in prevalence rates in various parts of the world indicate that MS is triggered by an exogenous factor such as a virus. Compston et al., Epidemiology and genetics of multiple sclerosis; Curr. Opin. Neurol. Neurosurg., 5:175 (1992). The low rate of concordance (20-30%) in monozygotic twins in which one has MS suggests that an exogenous factor, possibly a virus, as well as host genetics, plays a role in pathogenesis of the proposed animal models of CNS demyelination, Theiler's murine encephalomyelitis (TME) has received wide attention. Infection of susceptible strains of mice, (SJL/J), prototypic strain, with Theiler's murine encephalomyelitis virus (TMEV) results in virus persistence and chronic primary immune-mediated demyelination. Intracerebral infection with TMEV results in acute encephalitis, characterized by viral replication in neurons and inflammation in the brain. This acute infection is followed by a progressive primary demyelinating disease of the spinal cord (beginning 10 to 14 days after infection), characterized by viral persistence in macrophages, astrocytes, and oligodendrocytes. Studies of this model system have shown that chronic infection with TMEV results in demyelinating disease that has many similarities to MS.
As in MS, during the chronic phase of TMEV infection, the pathological abnormalities are limited to the CNS. The histological appearance is characterized by primary demyelination. In addition, as in the human disease, inflammatory cells and macrophages are intimately involved in the demyelinating process. After a long incubation period, this results in spasticity, weakness of the lower extremities, and bladder incontinence. The pathological change in the spinal cord is also characterized by recurrent episodes of acute demyelination superimposed on a chronic progressive disease that mimics the exacerbations and remissions observed clinically in the human disease. See, Rodriguez et al., Theiler's murine encephalomyelitis: A model of demyelination and persistence of virus, Crit. Rev. Immunol., 7:325 (1987). The TMEV murine model has provided an excellent way to test various therapeutic modalities to prevent or inhibit demyelination. Immunosuppression by using cyclophosphamide, antilymphocyte serum, cyclosporin, monoclonal antibodies (mAbs) to immune-response gene products (I-A), and mAbs to CD4 or CD8 has been shown to diminish the extent of demyelinating disease.
Administration of recombinant human or mouse tumor necrosis factor alpha (TNF-.alpha.) inhibits TMBV-induced demyelination in susceptible SJL/J mice without affecting virus replication in the CNS. TNF-.alpha. is also made by some activated T cells. Paya et al., Int'l Immunol., 2:909 (1990). These studies indicate that manipulation of the immune response by using pharmacologic agents, mAbs, or recombinant biologic products may influence the extent of demyelinating disease.
Recently, the role of interleukin-6 (IL-6) in the pathogenesis of inflammatory diseases of the CNS, including viral infections and MS, has been investigated. IL-6 is a cytokine of approximately 26 kD that is synthesized by mononuclear phagocytes, vascular endothelial cells, fibroblasts, and other cells in response to IL-1 and, to a lesser extent, TNF. IL-6 is one of the major mediators of the immune response, with pleiotropic effects on many different target cells. Along with TNF-.alpha., IL-1, and IFN .gamma., IL-6 belongs to a family of endogenous mediators in the reaction of the host to injury or infection referred to as the acute phase response. Astrocytes produce IL-6, and IL-1.beta. and TNF-.alpha. provide a strong inducing signal for IL-6 production. IL-6 mRNA and IL-6 receptor mRNA have been localized by in situ hybridization to neurons and astrocytes of rat brain. Astrocyte-produced IL-6 has been proposed to play a role in augmenting intracerebral immune responses. Increased levels of IL-6 have been detected in the CNS of mice suffering from the lethal forms of experimental autoimmune encephalomyelitis, an autoimmune model of MS. Gijbels et al., Eur. J. Immunol., 20:233 (1990). Neurotrophic viruses, such as Newcastle disease virus, trigger IL-6 as well as TNF-.alpha., IFN-.alpha., and TFN-.beta. production by astrocytes. Laboratory viruses Sendai, Mengo, and Newcastle disease virus stimulate IL-6 production in fibroblasts in a dose dependent manner. Infection of human skin fibroblasts in culture by dengue virus results in the production of IL-6, as well as IFN-9 and granulocyte-macrophage-CSF. Increased transcription of IL-6 has been detected in the brain of mice with chronic coxsackie B1 virus infection. IL-6 is produced in vitro in mouse brain endothelial cells and astrocytes after infection with the demyelinating variant of mouse hepatitis virus, a Coronavirus. Joseph et al., J. Neuroimmunol., 42:47 (1993). IL-6 is produced in the CNS of mice infected with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus. In vitro assays demonstrate that microglia and astrocytes infected by LCMV secrete IL-6, suggesting that IL-6 may be involved in repair mechanisms initiated in the course of viral-induced CNS damage. Frei et al., Eur. J. Immunol., 19:689 (1989).
IL-6 has been implicated in the pathogenesis of human inflammatory CNS diseases. Increased plasma and cerebrospinal fluid levels of IL-6 have been demonstrated in patients with MS (Frei et al., J. Neuroimmunol., 31:147 (1991)), HTLVI-associated myelopathy, and bacterial meningitis. Elevated levels of IL-6 have been detected in the cerebrospinal fluid of patients with CNS involvement from systemic lupus erythematosus and systemic vasculitides. Patients infected with HIV-1 produce elevated levels of IL-6, IL1, and TNF-.alpha., raising the possibility that these cytokines play a role in AIDS nervous system disease.
Although IL-6 has been implicated in viral-induced damage repair mechanisms, a role for IL-6 in therapeutic suppression of CNS demyelination in disorders such as MS has not been postulated. Clearly, it would be desirable to identify any factor that suppresses CNS demyelination, and any such factor would thus be a candidate for treatment of MS and other CNS demyelination disorders.